This is a renewal of a 15-year program for studies of cystic fibrosis (CF). Its objectives are: 1) elucidation of pathophysiology of CF with the goal of identifying the basic defect and 2) improving therapy. The proposed program has been developed around a core of 430 CF patients, and extensive research facilities and expertise in the Pediatric Department-based CF Center. Investigators with related interests and expertise in Medicine, Pathology, Anatomy, Biochemistry, Microbiology, Pharmacology, Macromolecular Science and Biomedical Engineering will participate in the work, many of whom have already established CF related research or collaborative efforts with one of the principal investigators in this program. Proposed basic science projects will attempt to identify or understand: 1) abnormal cell-mediated immunological mechanisms or abnormalities of alveolar macrophage function responsible for chronic pseudomonas lung infection, 2) the basis for antibiotic resistance of pseudomonas, 3) alterations in structure and function of tracheobronchial mucus glycoproteins and control of mucus secretion, 4) circulating and secretory factors, especially polyamines and related substances, which may be responsible for exocrine abnormalities, 5) pleural space mechanics. Clinical projects include: 1) longitudinal assessment of lung function in 700 patients as it relates to clinical status and medical history, 2) studies of exercise conditioning and its effect on well-being and lung function, 3) assessment of aminoglycoside therapy of pseudomonas infection and trials to improve their usefulness, 4) studies of EDTA in controlling lung infection with pseudomonas, 5) evaluation of echocardiography for early detection of pulmonary hypertension and as a guide to early intervention, 6) assessment of carbohydrate metabolism. These projects will depend on 8 core facilities, which will provide administrative support, coordinate patient participation and acquisition of patient specimens, and provide for computer, pulmonary function, endoscopic, microbiologic, morphologic, and large instrument services. This integrated approach will significantly enhance productivity and the likelihood of success of the overall project.